Hypercalcemia in Urological Malignancies: A Review

Hypercalcemia is an uncommon occurrence in urological malignancies except for renal cell carcinoma. However, when seen, it is usually associated with advanced disease and both the osteolytic as well as humoral mechanisms may be causative. Owing to its rarity, hypercalcemia can be easily missed during the initial evaluation of a patient with urologic malignancy. Our article aims to highlight the mechanisms associated with hypercalcemia in malignancy, in general, and review the available literature on hypercalcemia in urological malignancies. We also aim to discuss the management options in case of such an unusual occurrence in any urological cancer.


Introduction
Hypercalcemia is an uncommon occurrence in urological malignancies except for renal cell carcinoma (RCC). However, when seen, it is usually associated with advanced disease and both the osteolytic as well as humoral mechanisms may be causative. Owing to its rarity, hypercalcemia can be easily missed during the initial evaluation of a patient with urologic malignancy.
We hereby discuss hypercalcemia and its mechanisms of action and also enlist a comprehensive review of the literature in hypercalcemia in individual urological malignancies.

Method
Literature on the current topic was garnered via an extensive PubMed/Medline search employing the MeSH terms-hypercalcemia, urological malignancies, humoral hypercalcemia of malignancy, direct osteolytic hypercalcemia, hypercalcemia in renal cell cancer, hypercalcemia in bladder cancer, hypercalcemia in penile cancer, hypercalcemia in prostate cancer, hypercalcemia in testicular cancer, and hypercalcemia in urological malignancy.
All articles encompassing any of the above MeSH terms, in relation to urological malignancies, were included in the review. serum calcium level needs to be corrected as per the albumin levels of the patient. Corrected serum calcium can be calculated as: CSC = 0.8 × (4 -serum albumin) + serum calcium. Based on the level of corrected calcium level in blood, it can be classified as mild (Ca-10.5-11.9), moderate (Ca-12-13.9), and severe hypercalcemia (Ca > 14). Corrected serum calcium levels of more than 15 mg/dl are considered as a medical emergency and need immediate correction.

Symptoms of Hypercalcemia
Mild hypercalcemia can itself be asymptomatic or symptomatic associated with lethargy and/or skeletal pain. Moderate to severe hypercalcemia, on the other hand, may cause neurocognitive symptoms, significant volume depletion, acute renal insufficiency, and even death, particularly in severe cases. 1,2 The common symptoms of hypercalcemia may be classified as: a) Neurological symptoms (lethargy, weakness, confusion, coma). b) Gastrointestinal symptoms (constipation, nausea, anorexia, gastric ulcer, pancreatitis) or c) Renal symptoms (polyuria, nocturia, dehydration, stone). d) Others: Life-threatening arrhythmias or cardiac arrest (with severe hypercalcemia).

Hypercalcemia in Malignancy
The most common cause of hypercalcemia, per se, is hyperparathyroidism. Hypercalcemia in hyperparathyroidism is usually mild, asymptomatic, and long-standing. Rapidly increasing hypercalcemia should however increase the suspicion of malignancy.
The estimated prevalence of hypercalcemia in malignancy is 1.46-2.74% 2 and the most common malignancies associated with hypercalcemia are lung carcinoma, multiple myeloma, and RCC. Hypercalcemia is usually associated with an advanced stage of malignancy and is considered a poor prognostic factor.
The incidence of hypercalcemia in different malignancies as seen in the study conducted with electronic health records (EHR) data using the Oncology Services Comprehensive Electronic Records (OSCER) database is shown in Table 1. 3

Mechanism of Hypercalcemia in Malignancy
Hypercalcemia in malignancy can be due to several mechanisms. The two most common causes of hypercalcemia in malignancy are humoral hypercalcemia and direct osteolytic hypercalcemia.
a) Humoral hypercalcemia of malignancy (HHM): The release of the mediators by the tumor that causes bone resorption and subsequently increased serum calcium without the tumor directly invading the bony tissue is called HHM.
The term HHM was first proposed by Fuller Albright in 1941 4 and it specifically refers to parathyroid hormone-related peptide (PTHrP) mediated hypercalcemia. It constitutes about 80% of hypercalcemia in malignancies 5 and is commonly seen in squamous cell carcinoma of the esophagus, head and neck, lung, cervical cancers as well as in RCC, bladder cancer, breast cancer, endometrial and ovarian cancers.
Parathyroid hormone-related peptide is normally secreted by mesenchymal stem cells. It functions in endocrine, paracrine, autocrine, and intracrine manners and has a role in endochondral bone development, tooth eruption, and mammary gland development. When secreted by tumor cells, it can cause hypercalcemia.

Main Points
• Since hypercalcemia is a rare occurrence in urological malignancies, it can be easily missed during the initial evaluation of the patient.
• When seen, it is usually associated with advanced disease and both the osteolytic as well as humoral mechanisms may be causative.
• Our article aims to highlight the mechanisms associated with hypercalcemia in malignancy and review the available literature on hypercalcemia in urological malignancies and enlist their respective managements and outcomes. In osteolytic hypercalcemia, there is a direct invasion of bone by the tumor, causing osteolysis and subsequent hypercalcemia.
Local osteolytic hypercalcemia is seen in 20% of malignancies and is commonly seen in multiple myeloma and breast cancers. 6 It is thought to be due to the release of local cytokines which cause excessive osteoclast activation and bone resorption, mediated through RANK/RANKL complex. Besides these, other less common causes of hypercalcemia of malignancies are extrarenal production of 1,25(OH)2D, ectopic parathyroid production, or associated primary hyperparathyroidism. 7

Hypercalcemia in Urological Malignancies
Hypercalcemia is an uncommon occurrence in urological malignancies except for RCC. However, when seen, it is usually associated with advanced disease and both the osteolytic as well as humoral mechanisms may be causative.
Owing to its rarity, hypercalcemia can be easily missed during the initial evaluation of a patient with urologic malignancy. Any patient with advanced urologic malignancy, in particular, with symptoms of lethargy, weakness, or gastrointestinal distress should be evaluated with a suspicion of having hypercalcemia. Figure 1 depicts the number of cases of Urological malignancies, with hypercalcemia, reported in the literature, to date. Figure 2 depicts the decade-wise distribution of these cases, as reported in the literature.

Renal Cell Carcinoma
The most common presentation of RCC is the triad of hematuria (50-60%), abdominal pain (40%), and palpable mass (30%). 8 Renal cell carcinoma is also the most common urologic malignancy associated with various paraneoplastic syndromes, seen in nearly 30% of patients, namely elevated erythrocyte sedimentation rate (ESR), hypercalcemia, polycythemia, hepatic dysfunction (Stauffer's syndrome), amyloidosis, hypertension, and fever. 9 Most of these remit with the treatment of the primary disease.
Approximately 17% of all patients with RCC develop hypercalcemia during the course of their disease. 10 Humoral hypercalcemia of malignancy is seen to affect 13-20% of these. 11  in bladder cancer was found to be associated with paraneoplastic syndromes, in their study. 12 Albright in 1941 postulated that hypercalcemia was because of a humoral factor secreted by the tumor cells. 13 In the late 1980s, this substance was identified and named as PTHrP. It is seen to be elevated in up to 15% of all patients with RCC. Other humoral factors that have also been associated with hypercalcemia in RCC include IL-6, IL-1, TNFα, transforming growth factor-alpha and beta, and prostaglandins. 13,14 IL-6 has been shown to activate osteoclastic bone resorption but it is unclear whether this cytokine causes hypercalcemia directly or by the effect of PTHrP. It has been seen to act synergistically when coexpressed with PTHrP. Other causes of hypercalcemia in cases of RCC include medications like premarin, lytic bone lesions, and ectopic PTH secretion.
Elevated corrected calcium concentration may be considered as a potential biomarker for assessing the prognosis of this disease. However, though an association has been found, this has not yet been proven in case of localized RCC. A study by Fahn  The role of nephrectomy in the management of hypercalcemia in metastatic renal carcinoma is not well established. In the era before cytokine therapy, cytoreductive surgery was commonly practiced for hypercalcemia of RCC. Nephrectomy has been shown to temporarily ameliorate hypercalcemia in a subgroup of patients with metastatic renal cancer and hypercalcemia in a study by Walther et al. In their study, a decrease in serum calcium corrected for albumin occurred in 9 of 11 patients at 1 to 4 weeks after nephrectomy and in 7 of 12 patients at 5 to 16 weeks after nephrectomy. 17 However, with the emergence of targeted therapy for advanced RCC, the role of cytoreductive nephrectomy has become a debated topic. Few studies have shown that sunitinib, an oral multitargeted tyrosine kinase inhibitor, normalizes hypercalcemia in a metastatic RCC thus eliminating the need for surgery in such patients. 18 Table 2 lists the reports of RCC with hypercalcemia, in the literature, to date.

Bladder Cancer
Bladder cancer typically presents with macroscopic hematuria. Most bladder cancers are urothelial (transitional cell) malignancies followed by occasionally squamous cell and adenocarcinoma. Hypercalcemia in bladder cancer is not a common occurrence and if present it is usually associated with the bony metastasis or large tumor volume. Very few cases of bladder cancers associated with raised PTHrP have been reported in the literature. The outcome of such malignancies is usually very poor. Although most cases of urothelial carcinoma associated with paraneoplastic hypercalcemia tend to be high grade and aggressive in nature with a poor prognosis, 28 few have been reported without any metastasis. 29,30 Outcome of such tumors is reported as usually good, as hypercalcemia tends to resolve after radical cystectomy. 31 Serum calcium levels normalize during the immediate postoperative period itself. However, regular serum calcium level monitoring is needed in such patients because the recurrence of hypercalcemia may likely be a surrogate sign of tumor recurrence in the lymph nodes or even bony metastasis. 32 There is, however, no preferred treatment for hypercalcemia associated with the recurrence of such malignancies. Radiotherapy or chemotherapy may be helpful to ameliorate the symptoms, but these patients are usually poor candidates for chemotherapy. Intravenous hydration, bisphosphonates, calcitonin, and denosumab are the options available to attempt a decrease calcium levels.
Few cases of small cell carcinoma of bladder causing hypercalcemia have also been reported in the literature. 33,34 Cesar V Reyes reported 2 cases of small cell carcinoma of bladder. In both cases, despite treatment, the disease progressed and patients died. Table 3 lists the literature available on bladder cancer with hypercalcemia.

Penile Carcinoma
Most penile carcinomas are localized to the prepuce or glans penis. The regional disease is seen in about 13% of cases and distant metastasis is seen in 2.3%. Although squamous cell carcinomas (SCC) are collectively the most common cause of HHM, SCC of the penis rarely presents with hypercalcemia. Like in any other urologic malignancy, hypercalcemia in penile carcinoma tends to be associated with advanced disease and/or bony metastasis.
Hypercalcemia has also been reported without bony metastasis which is attributable to the paraneoplastic syndrome due to the expression of PTHrP. 41 Penile malignancy with hypercalcemia without bony metastasis was first reported by Anderson et al in 1965. The case was a non-metastatic SCC of penis which was managed with surgical removal of tumor. The serum calcium level returned to normal within 24 hours of removal of the primary penile lesion. However, the level of PTHrP was undocumented in this case. 42 Malakoff and Schmidt described a patient with metastatic penile carcinoma which was complicated with serious hypercalcemia due to secretion of PTH. Management of the hypercalcemia by oral biphosphonates, hydration, and diuretics showed only a temporary response. There was transient response to furosemide-induced dieresis and he was refractory to treatment with oral inorganic phosphates and mithramycin. Ablation of the primary tumor did not affect his hypercalcemia. His serum calcium stabilized and became normal after external irradiation and parenteral bleomycin therapy. However, this response was only temporary as there was the progression of the tumor. 43 In another case reported by Trejo et al. hypercalcemia in penile carcinoma was associated with PTHrP secretion. It was managed initially with vigorous hydration and loop diuretics without achieving a satisfactory calcium level. A dose of 4 mg zoledronic acid was therefore infused, resulting in a remarkable  There are also few case reports of penile carcinoma presenting with hypercalcemia due to ectopic production of parathyroid hormone. Sardinas et al reported a case of penile carcinoma with hypercalcemia with elevated PTH and low/normal PTHrP. Lesional fluid aspirated during the biopsy contained very high levels of PTH, thus confirming its ectopic source from this metastatic squamous cell neoplasm. 45 Gandhi et al reported a case of extensive visceral calcification demonstrated on 99m Tc-MDP bone scan in patient with carcinoma penis and hypercalcemia of malignancy. These metastatic calcifications are mostly reversible after normalization of calcium metabolism and renal function with the disappearance of the increased uptake on bone scan. 46 Table 4 lists the literature available on penile cancer with hypercalcemia.

Prostate Cancer
Prostate cancer is the second most common cancer and the fourth most common cause of cancer death in men. Bony metastasis and associated skeletal events like pathological fractures and cord compressions are not uncommon in metastatic carcinoma of the prostate. 2 However, hypercalcemia is a rare manifestation of prostate cancer because these metastasis are osteoblastic. In a retrospective study conducted between 2009 and 2013 using the OSCER warehouse of EHR, the rates of malignancy-induced hypercalcemia were the lowest among patients with prostate cancer, ranging from 1.4% to 2.1%. 2 The exact pathophysiology of hypercalcemia in prostate cancer is unknown although humoral hypercalcemia and osteolytic hypercalcemia both have been proposed.
A study by Iwamura et al suggested that PTHrP may play a significant role in the growth of prostate cancer by acting locally in an autocrine fashion. Their study showed that all prostate cancer cell lines from different sources expressed PTHrP immunoreactivity as well as evidence of DNA synthesis. The cancer cell line derived from bone metastatic lesions secreted significantly greater amounts of PTHrP than did the cell line derived from the metastasis in the brain or in the lymph node. These findings suggest that PTHrP production may confer some advantage on the ability of prostate cancer cells to grow in bone. However, in spite of widespread expression of PTHrP in prostate cancer, hypercalcemia is still not so common probably due to counteraction of other factors like simultaneous secretion of calcitonin. 49 Some studies have shown that hypercalcemia in prostate cancer is associated with unusual histology, particularly neuroendocrine differentiation of adenocarcinoma. A study by Takashi et al showed that neuroendocrine development as a result of androgen deprivation therapy caused hypercalcemia due to PTHrP secretion, which was lethal. Thus, early detection and treatment of neuroendocrine differentiation would improve prognosis. However, Prostate Specific Antigen (PSA) is not an appropriate marker for detecting neuroendocrine differentiation. Hence periodic monitoring of neuroendocrine markers such as neuronspecific enolase should be considered. 50 In a case reported by Alhatemi et al. a case of carcinoma of the prostate with hypercalcemia had osteoblastic lesions on the bone scan, hence ruling out the local osteolytic bone destruction theory for hypercalcemia. Furthermore, PTHrP was not significantly elevated in this patient, PTH levels were normal and histopathology showed no evidence of mosaicism or neuroendocrine dedifferentiation. These findings in aggregate tell us that an exact pathophysiologic mechanism leading to hypercalcemia in prostate cancer is still unclear. 51 There can be an interplay of different factors apart from these which need to be proven by future research. Table 5 lists the literature available on prostate cancer with hypercalcemia.

Testicular Tumor
Sixty percent of the testicular tumors are seminomas. Very few cases of seminoma associated with hypercalcemia have been reported, and their association with PTHrP has not been studied in those few reported cases. In contrast to other urologic malignancies with hypercalcemia, testicular tumor with hypercalcemia usually has a good prognosis. 53 Table 6 lists the literature available on testicular cancer with hypercalcemia.

Conclusion
Hypercalcemia although generally rare in urologic malignancies may sometimes be seen in advanced cases. Humoral hypercalcemia of malignancy due to raised PTHrP is the most common cause of hypercalcemia followed by osteolytic hypercalcemia. The mainstays of treatment are hydration, bisphosphonates, and calcitonin. Treatment of the primary is necessary to treat as well as to prevent the recurrence of hypercalcemia.

Declaration of Interests:
The authors have no conflict of interest to declare.

Funding:
The authors declared that this study has received no financial support.  A, absent; P, present; U, undocumented; N, normal; NA, not available; E, elevated.